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Expression of Bgp1a, a glycoprotein that serves as receptor for mouse hepatitis virus-A59 has been analyzed in various mouse tissues and correlated with the pathogenicity that this virus induces in the corresponding organs. Expression of Bgp1a was observed in many cells of epithelial origin, including hepatocytes and endothelial cells. It was also shown on macrophages and B lymphocytes. Bgp1a localization may easily explain infection and lysis of some cell types like hepatocytes. In contrast, other cell types that express the viral receptor are not infected after in vivo inoculation with mouse hepatitis virus-A59, which may be due to inaccessibility of the receptor to the virus during mouse infection, or to resistance to this virus in some cell types. This may account for the ability of the blood-brain barrier to prevent mouse hepatitis virus-A59 spreading into the central nervous system. In other organs, the virus may induce pathogenesis indirectly, resulting in the destruction of cells that do not express Bgp1a, like thymic lymphocytes, or else impair cell functions such as cytokine and immunoglobulin production by macrophages and B lymphocytes, respectively.

Mouse hepatitis virus, strain A59 (MHV-A59), is a coronavirus that triggers in susceptible mice a wide variety of pathologies, including hepatitis, thymus involution, B lymphocyte polyclonal activation and, after intra-cerebral inoculation, transient demyelination. One receptor that mediates entry of the virus into target cells has been identified: it is a glycoprotein of the carcinoembryonic antigen family, called Bgp1a. The availability of antibodies recognizing this molecule permits the analysis of its cellular expression and of the relationship between receptor expression and pathology induced by the virus. Bgp1a is found on epithelial and endothelial cells as well as on B lymphocytes and macrophages. In the liver, Bgp1a expression correlates well with infection of hepatocytes and endothelial cells, leading to the development of hepatitis. However, other cells expressing this molecule, such as central nervous system endothelial cells, are not infected by the virus. This observation may explain how the blood-brain barrier prevents dissemination of MHV-A59 from the general circulation into the brain. Thymic atrophy results from apoptosis of immature double-positive T lymphocytes which might be caused indirectly by infection of a small proportion of thymus epithelial cells that express Bgp1a rather than by infection of T cells that do not express the receptor. Finally, polyclonal activation of B lymphocytes, leading to increased secretion of antibodies of the IgG2a isotype, involves a cascade of events, including cytokine secretion, that may result from the interaction of MHV-A59 with B cells and macrophages that express Bgp1a. Therefore, after viral infection, cellular expression of Bgp1a may have different results: cell lysis; alteration of cellular functions that may lead to indirect death of other cell types, or resistance to infection.

BALB/c mice develop a neurologic demyelinating disease after inoculation of mouse hepatitis virus (MHV), strain A59, by the intracranial, but not by the intraperitoneal route. To determine the mechanisms that prevent virus spreading through the blood-brain barrier, we analyzed expression of MHVR, a glycoprotein that serves as receptor for mouse hepatitis virus on endothelial cells of cerebral blood vessels. Our results indicated that MHVR was strongly expressed on the endoluminal pole of these cells. In addition, a direct virus binding assay showed that mouse hepatitis virus was able to bind endothelial cells via this receptor. Despite this expression of a functional viral receptor, in normal mice infected with mouse hepatitis virus by the contra-peritoneal route, no in vivo viral replication could be detected in endothelial cells from the brain, contrasting with the equivalent cells from the liver. However, shortly after i.v. administration of sodium dodecylsulfate detergent to the mice, virus infection of some cerebral endothelial cells was detected in a few mice. As a consequence of detergent treatment, virus infection was able to cross the blood-brain barrier. These results suggest that the protective role of the blood-brain barrier against spreading of mouse hepatitis virus A59 into the central nervous system is determined by a specific restriction of viral entry into the endothelial cells of cerebral origin.

Mouse hepatitis viruses (MHV) diversely affect immune responses, depending on the viral strain and the mouse genetic background. Here, we studied the effect of MHV-A59 infection on B cell responses of 129/Sv and CBA mice. Our results indicate that in these strains, MHV-A59 induces spleen cell activation that leads to enlargement of the spleen without structural alteration. Infection triggers production by B lymphocytes of large amounts of immunoglobulin G2a, mostly without viral specificity. This polyclonal immunoglobulin production is dependent on the presence of functional T helper cells. This polyclonal B lymphocyte activation induced by MHV-A59 infection can have pathological implications, such as the enhancement of concomitant autoimmune reactions.

Background: The receptor for the murine coronavirus mouse hepatitis virus (MHV)-A59, called MHVR or Bgp1a, is a glycoprotein in the carcinoembryonic antigen family of the Ig superfamily. Biliary glycoprotein (Bgp) isoforms play a role in cell adhesion, bile acid transport, and ecto-ATPase activity. MHV-resistant SJL/J mice express a different allele of Bgp1 called Bgp1b. Analysis of the tissue and cellular distribution of Bgp1 proteins can therefore provide new insight on both cellular functions and MHV-A59--induced pathogenesis., Experimental Design: Bgp1 expression was analyzed in the digestive, respiratory, endocrine, urinary, and central nervous systems of adult BALB/c and SJL/J mice by immunocytochemistry and immunoelectron microscopy using a monoclonal Ab specific for the N-terminal domain of the Bgp1a proteins and polyclonal rabbit anti-Bgp1, which recognizes both the Bgp1a and Bgp1b proteins. The function of Bgp1 proteins as viral receptors was tested on tissue sections by a virus binding assay. MHV-A59 replication was analyzed by immunocytochemistry., Results: Bgp1 expression was observed on membranes of epithelial cells (including hepatocytes, intestinal, endocrine, and respiratory epithelial cells), kidney proximal tubules, and endothelial cells in many tissues. It was usually localized at the apical pole of the cells and, when present, on the brush borders and the cilia. A new direct virus binding assay showed that MHV attachment onto cells correlates with Bgp1 expression. Viral infection was detected in hepatocytes, lymphoid tissue, and the exocrine pancreas but not in endocrine cells, enterocytes, kidney, or respiratory cells. In the central nervous system, no immunolabeling of neurons or glial cells was found with anti-Bgp1 Ab., Conclusions: Bgp1 proteins are present on BALB/c and SJL/J epithelia and endothelia. These glycoproteins might be involved in cell-to-cell contacts, for example between hepatocytes. On BALB/c mice, Bgp1a expression is consistent with the tropism of MHV-A59 for the liver. However, Bgp1a was also expressed on cells that were not infected by MHV-A59.

Mouse hepatitis virus A59 (MHV-A59) infection of adult BALB/c mice induced a severe, transient atrophy of the thymus. The effect was maximal at 1 week after infection, and thymuses returned to normal size by 2 weeks after infection. There was no effect of glucocorticoids, since thymus atrophy was also found in adrenalectomized, infected mice. In infected thymus, immature CD4+ CD8+ lymphocytes were selectively depleted, and apoptosis of lymphocytes was increased. The MHV receptor glycoprotein MHVR was detected on thymus epithelial cells but not on T lymphocytes. In a small number of stromal epithelial cells, but in very few lymphocytes, the viral genome was detectable by in situ hybridization. These observations suggested that MHV-A59-induced thymic atrophy results not from a generalized lytic infection of T lymphocytes but rather from apoptosis of immature double-positive T cells that might be caused by infection of a small proportion of thymus epithelial cells or from inappropriate secretion of some factor, such as a cytokine.